Methods of treating pain with n**alpha-phthaloyl-alpha-amino acid amides



United States Patent US. Cl. 424274 3 Claims ABSTRACT OF THE DISCLOSURE This invention relates to novel methods and compositions for effecting analgesia in mammals. More particularly, the present invention pertains to a method of effecting analgesia by administering an N -phthaloyl-uamino acid amide as hereinafter defined.

The N-phthaloyl-a-amino acid amides employed in this invention may be represented by the following Formula I:

ONE: 0 ll I wherein R is hydrogen or lower alkyl.

By the term lower alkyl is intended a group comprising a straight or branched hydrocarbon chain containing of from one to about six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, t-butyl, pentyl, isopentyl, hexyl and the like.

According to this invention, the above compounds are administered to mammals for the purpose of treating various pain manifestations as for example those associated with the common cold, bursitis, general headache, minor injuries such as sprains and bruises, dysmenorrhea, toothache and the like. While they may be administered via any of the usual routes, e.g. parenterally, rectally or the like, the preferred route is orally. For such oral administration, the incorporation of a pharmaceutical carrier for the formation of a pharmaceutical composition is highly desirable.

Such suitable compositions include, without limitation, tablets, capsules, powders, solutions, suspensions, sustained release formulations and the like.

By the administration of these compounds in dosages of up to 50 ing/kg. of body weight per day, preferably about 5 mgJkg. to about 30 mg./kg., pain thresholds can be effectively raised as the following test illustratively shows:

150 mg./kg. of N -phthaloyl-DL-alanylamide suspended in carboxymethyl cellulose were administered to mice and the analgesic activity was determined by the hot plate test, using a plate temperature of 57 C. The compound was given orally one-half hour before placing the mice which had fasted for 18 hours on the plate. The end point was determined by lifting of a hind paw from the plate. The outstanding increase of the pain threshold was +237.5% in comparison with non treated animals.

The acute toxicity was determined after peroral administration according to the method of Litchfield-Wilcoxon. The LD mg./kg., for instance, was higher than 1000 for N -phthaloyl-DL-alanylamide.

1 J. Pharm. Exp. Therap. 96, pp. 99-113 (1949) 3,452,141 Patented June 24, 1969 ical activity in comparison to the structurally related thalidomide on mature female New Zealand rabbits. Accord ing to H. M. Wuest, E. B. Sigg and I. Fratta, Life Sci. 3, 721 (1964) and I. D. Fratta, E. B. Sigg and K. Maiorana, Toxic Appl. Pharmac. 7, 268 (1965), the rabbits were conditioned for three weeks (temperature, 70 F.; humidity 55%) and mated, using four genetically known male rabbits. Test drugs and placebo (starch) were administered per os in gelatin capsules from day 4 after copulation to day 16, with day 1 considered as the day of mating. On the 31st day of gestation, caesarean section was performed under chloroform anesthesia and the fetuses were removed. After macroscopic examination, cross sections were made according to the method of Wilson. (J. G. Wilson: Teratology Principles and Techniques, p. 262, University of Chicago Press, Chicago, (1965).)

The effect of the tested compound on embryonic development in rabbits was not significantly different from the controls, while with thalidomide, the teratogeny rose up to 60%.

Depending on the nature of the specific condition, this invention may be practiced in conjunction with the administration of other therapeutic agents. Thus, for eX- ample, the compounds described herein may be combined with aspirin, calfein, barbiturates, phenacetin, amphetamines or the like as well as combinations thereof and advantageously administered in such combination.

To produce dosage units for peroral application, the compositions of this invention may be combined, e.g. with solid pharmaceutically acceptable pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, corn starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatin, also lubricants such as magnesium or calcium stearate or polyethylene glycols (Carbowaxes) of suitable molecular weights may be added, to form tablets or press coated tablets. The latter are coated for example, with concentrated sugar solutions which can contain e.g. gum arabic, talcum and/or titanium dioxide, or they are coated with a lacquer dissolved in easily volatile organic solvents or a mixture of organic solvents. Dyestuffs can be added to these coatings, for example, to distinguish between different contents of active substance.

Hard gelatin capsules contain, for example granulates of the instant composition with solid pulverulent carriers such as e.g. lactose, saccharose, sorbitol, mannitol and further starches such as potato starch, corn starch or amylopectin, cellulose derivatives or gelatin, as well as magnesium stearate or stearic acid.

Suppositories containing a compound of the present invention are readily obtained by techniques well known to those skilled in the art of compounding dosage forms. A compound of the present invention is dispersed in a carrier such as cocoa butter and the suppositories formed in the usual way.

This invention contemplates a method for effecting analgesia which comprises administering to mammals suffering with pain a therapeutic dose of a compound of Formula I.

Also contemplated by this invention is a composition for use to effect analgesia comprising a pharmaceutical carrier and a compound of Formula I as defined in the method above, in dosage unit forms acceptable for internal administration.

The compounds used according to this invention can be prepared according to E. Radde: Ber. deut. Chem. Ges. 55, 3174 (1922) by treating the substiuted a-amino acid, for example phthaloyl-DL-a-alanine with a halogenating agent thereby preparing the correspondingly substituted amino acid halides (preferably the chloride) which can be converted to the desired amide by treating it with gaseous ammonia in an inert solvent or ammonia hydroxide.

The following examples are given by Way of illustrating the process for the production of the compound and the composition without limiting the scope thereof in any way. The temperatures are given in degrees C.

EXAMPLE I Phthaloyl-DL-a-alanylamide A mixture of 9.6 g. of phthaloyl-DL-u-alanine, 200 ml. thionyl chloride and 5 drops of pyridine was refluxed f r two hours. The solution was taken to dryness under vacuum and the oily residue was dissolved in 150 ml. of dry tetrahydrofuran. A trace of insoluble material was removed by filtration. The solution was cooled in a Dry- Ice-acetone bath and gaseous ammonia was passed in for ten minutes. Cooling was continued for one-half hour and the contents were then allowed to come to room temperature. The resultant solid was removed by filtration. The solid was slurried in 200 ml. of water and then filtered. The solid was washed with 200 ml. of dilute ammonium hydroxide and then dried to yield 6.55 grams (68%) of a white solid, M.P. 2140-2155". Recrystallization from methanol yielded an analytical sample, M.P. 214.5215.5

Analysis, C H N O M01. weight 218.21. Calcd.: C, 60.44; H, 4.62; N, 12.84. Found: C, 60.76; H, 4.89; N, 12.53.

EXAMPLE II Phthaloyl glyclyamide O O l] 0 -OH ii-NH I l N-C-H I I 11 i i t) o A mixture of 6.6 grams phthaloyl glycine, 200 ml. thionyl chloride, and 5 drops of pyridine were refluxed for 1 /2 hours. The excess thionyl chloride was removed under aspirator. Benzene was added and taken to dryness. The resulting yellow solid was dissolved in 200 ml. of dry tetrahydrofuran. A trace of undissolved solids were removed by filtration.

The tetrahydrofuran solution was cooled in a Dry-Iceacetone bath and ammonia gas was passed in the solution for ten minutes. The mixture was cooled for an additiona1 /2 hour, then the tempearture was allowed to rise to room temperature. The residue was filtered off. The solid was slurried in water and filtered. The solid was washed 4- with dilute ammonium hydroxide and dried to yield 4.74 g. (72%) of white solid, M.P. 260.5-2620. Four recrystallizations from alcohol yielded white needles M.P. 2625-2630. (Erich Radde, Ber. 55, 3174 (1922), M.P. 257.

EXAMPLE III Ingredient: Quantity/capsule, mg.

Phthaloyl-DL-u-alanylamide -200 Corn starch, U.S.P. 200

The above ingredients are mixed and introduced into a two-piece hard gelatin No. 1 capsule.

EXAMPLE IV Ingredient: Quantity/tablet, mg. PhthaIOyLDL-a-aIanyIamide 100-200 Corn starch, U.S.P. Lactose, U.S.P. Cab-O-Sil, M-5 4 Gelatin, U.S.P 5 Magnesium stearate, U.S.P. 1

The above ingredients, after being thoroughly mixed, are pressed into single scored tablets.

Any changes in conditions such as temperature, reaction time, pH value and quantities used obvious to those skilled in the art are considered within the scope of this invention.

What is claimed is:

1. The method of elfecting analgesia which comprises administering to a mammal suffering with pain an effective amount of a compound of the general formula:

0 II C R N-ltH-CONH;

wherein R is hydrogen or lower alkyl, or pharmaceutically acceptable, non-toxic acid addition salts thereof.

2. A method according to claim 1 wherein R is methyl. 3. A method according to claim 1 wherein R is hydrogen.

References Cited Life Sciences, 3 (9), pp. 987-992 (1964).

Chem. Abstracts, 41, 37586 (1947).

ALBERT T. MEYERS, Primary Examiner.

S. J. FRIEDMAN, Assistant Examiner. 

